Fused diazepines as agonists of the insulin-like 3 (insl3) peptide receptor rxfp2 and methods of use thereof

Abstract

Disclosed is a compound of formula (I), in which R1, R2, R3, R4, R5, X1, X2, X3, X4, and X5 are described herein. The small molecule compounds of formula (I) activate the functional activity of relaxin family peptide receptor 2 (RXFP2), thereby providing therapeutic treatments for a variety of disorders, such as a bone disorder, hypogonadism, cryptorchidism, polycystic ovary syndrome, cancer, infertility, or an ocular wound.

1 - 29 . (canceled) 
     
     
         30 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 X 1 , X 2 , and X 3  are the same or different and each is CH or N; 
 X 4  is an optionally substituted aryl or heteroaryl; 
 X 5  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         R 1  is hydrogen or alkyl; 
         R 2 , R 3 , R 4 , and R 5  are the same or different and each is hydrogen, alkyl, or halo; 
         each instance of R 6  is the same or different and is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonamido, carboxylato, —C(═NH)OH, aryl, heteroaryl, and 2-oxoazetidinyl; or 
         two instances of R 6  along with the cyclic moiety to which they are bound form phenyl, cycloalkyl, or —O—C(R 7 R 8 )—O—; 
         R 7  and R 8  are the same or different and each is hydrogen, alkyl, or halo; 
         l is 0 or an integer of 1 to 6; 
         m is 0 or 1; 
         n is 0 or an integer of 1 to 6; and 
         p is 0 or an integer of 1 to 4; 
       
       or a pharmaceutically acceptable salt and/or an enantiomer thereof. 
     
     
         31 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein X 1 , X 2 , and X 3  are each CH. 
     
     
         32 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein one of X 1 , X 2 , and X 3  is N and the remaining two are each CH. 
     
     
         33 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein R 1  is hydrogen. 
     
     
         34 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein R 2 , R 3 , R 4 , and R 5  are each hydrogen. 
     
     
         35 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein X 4  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein 
         each instance of R 9  is the same or different and is selected from the group consisting of alkyl, cycloalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, carboxylato, and —C(═NH)OH; or 
         two instances of R 9  along with the cyclic moiety to which they are bound form phenyl, cycloalkyl, or —O—C(R 7 R 8 )—O—; 
         R 10  is hydrogen or alkyl; and 
         q is 0 or an integer of 1 to 4. 
       
     
     
         36 . The compound of  claim 35  or a pharmaceutically acceptable salt and/or
 enantiomer thereof, wherein X 4  is 
 
       
         
           
           
               
               
           
         
         each instance of R 9  is the same or different and is selected from the group consisting of alkyl, cycloalkyl, halo, haloalkyl, hydroxy, cyano, nitro, haloalkoxy, alkylthio, alkylsulfonyl, and —C(═NH)OH; or 
         two instances of R 9  along with the cyclic moiety to which they are bound form —O—C(R 7 R 8 )—O—; and 
         q is 0 or an integer of 1 to 3. 
       
     
     
         37 . The compound of  claim 36  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein each instance of R 9  is the same or different and is selected from the group consisting of alkyl, cyclopropyl, fluoro, chloro, trifluoromethyl, and hydroxy; and q is 1 or 2. 
     
     
         38 . The compound of  claim 35  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 X 4  is 
 
       
         
           
           
               
               
           
         
         each instance of R 9  is the same or different and is selected from the group consisting of alkyl, cycloalkyl, halo, haloalkyl, nitro, amino, alkylamino, dialkylamino, and haloalkoxy; and 
         q is 0 or an integer of 1 to 2. 
       
     
     
         39 . The compound of  claim 35  or a pharmaceutically acceptable salt and/or
 enantiomer thereof, wherein X 4  is 
 
       
         
           
           
               
               
           
         
         R 9  is selected from the group consisting of alkyl, halo, and haloalkyl; and 
         q is 0 or 1. 
       
     
     
         40 . The compound of  claim 30 , or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein 
       
         
           
           
               
               
           
         
         X 5  is 
         each instance of R 6  is the same or different and is selected from the group consisting of alkyl, pyrrolidinyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonamido, and 2-oxoazetidinyl; or 
         two instances of R 6  along with the cyclic moiety to which they are bound form phenyl or —O—C(R 7 R 8 )—O—; 
         R 7  and R 8  are the same or different and each is hydrogen or halo; 
         l is 0; m is 1; n is an integer of 1 to 6; and 
         p is 0 or an integer of 1 to 4. 
       
     
     
         41 . The compound of  claim 40  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 (i) p is 1, and R 6  is fluoro, trifluoromethyl, cyano, trifluoromethoxy, difluoromethoxy, methylthio, methylsulfonyl, trifluoromethylsulfonyl, methylsulfon(methyl)amido, and 2-oxoazetidinyl; or 
 (ii) p is 2, and each instance of R 6  is the same or different and is selected from the group consisting of methyl, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, methoxy, trifluoromethoxy, and difluoromethoxy; or 
 two instances of R 6  along with the cyclic moiety to which they are bound form phenyl or —O—CF 2 —O—; or 
 (iii) p is 3, and each instance of R 6  is the same or different and is selected from the group consisting of methyl, fluoro, trifluoromethyl, cyano, and trifluoromethoxy; or 
 (iv) p is 4, and each instance of R 6  is the same or different and is selected from the group consisting of methyl and cyano. 
 
     
     
         42 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 X 5  is 
 
       
         
           
           
               
               
           
         
         each instance of R 6  is the same or different and is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonamido, carboxylato, —C(═NH)OH, aryl, heteroaryl, and 2-oxoazetidinyl; or 
         two instances of R 6  along with the cyclic moiety to which they are bound form phenyl or —O—C(R 7 R 8 )—O—; 
         R 7  and R 8  are the same or different and each is hydrogen, alkyl, or halo; and 
         either 
         (i) l is 0; m is 0; and n is an integer of 1 to 6; 
         (ii) l is 0; m is 1; and n is 0; or 
         (iii) l is an integer of 1 to 6; m is 1; and n is 0; 
         and 
         p is 0 or an integer of 1 to 3. 
       
     
     
         43 . The compound of  claim 42  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 each instance of R 6  is the same or different and is selected from the group consisting of hydroxy and alkoxy; or 
 two instances of R 6  along with the cyclic moiety to which they are bound form —O—CH 2 —O—. 
 
     
     
         44 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 X 5  is 
 
       
         
           
           
               
               
           
         
         each instance of R 6  is the same or different and is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonamido, carboxylato, —C(═NH)OH, aryl, heteroaryl, and 2-oxoazetidinyl; or 
         two instances of R 6  along with the cyclic moiety to which they are bound form phenyl; 
         l is 0; m is 0; and n is an integer of 1 to 6; and 
         p is 0 or an integer of 1 to 3. 
       
     
     
         45 . The compound of  claim 44  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 each instance of R 6  is the same or different and is selected from the group consisting of halo and haloalkyl; or 
 two instances of R 6  along with the cyclic moiety to which they are bound form phenyl; and 
 p is 0 or an integer of 1 or 2. 
 
     
     
         46 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 X 5  is 
 
       
         
           
           
               
               
           
         
         each instance of R 6  is the same or different and is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonamido, carboxylato, —C(═NH)OH, aryl, heteroaryl, and 2-oxoazetidinyl; or 
         two instances of R 6  along with the cyclic moiety to which they are bound form phenyl; 
         l is 0; m is 1; and n is 0; and 
         p is 0 or an integer of 1 to 3. 
       
     
     
         47 . The compound of  claim 46  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein
 each instance of R 6  is haloalkyl, or 
 two instances of R 6  along with the cyclic moiety to which they are bound form phenyl; and 
 p is 1 or 2. 
 
     
     
         48 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein the compound of formula (I) is an S-enantiomer. 
     
     
         49 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, wherein the compound of formula (I) is an R-enantiomer. 
     
     
         50 . The compound of  claim 30  selected from the compounds listed in Tables 1, 2, 3, 4, 5, and 6 of the specification, a racemic mixture thereof, or an enantiomer thereof. 
     
     
         51 . The compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof, that is 
       
         
           
           
               
               
           
         
       
     
     
         52 . A pharmaceutical composition comprising the compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof and at least one carrier. 
     
     
         53 . A method of treating a disorder mediated by relaxin family peptide receptor 2 (RXFP2) in a subject, the method comprising administering an effective amount of a compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof. 
     
     
         54 . The method according to  claim 53 , wherein the disorder mediated by RXFP2 is a bone disorder, hypogonadism, cryptorchidism, polycystic ovary syndrome, cancer, infertility, or an ocular wound. 
     
     
         55 . The method according to  claim 54 , wherein the bone disorder is osteoporosis, osteopenia, or osteogenesis imperfect, and/or the cancer is testicular cancer, prostate cancer, or thyroid cancer. 
     
     
         56 . A method of activating a functional activity of relaxin family peptide receptor 2 (RXFP2) in a subject comprising administering to the subject an effective amount of a compound of  claim 30  or a pharmaceutically acceptable salt and/or enantiomer thereof. 
     
     
         57 . The method of  claim 56 , wherein the activating results in growing bone or muscle in a subject.